Process for the preparation of benazepril hydrochloride

ABSTRACT

A process for the preparation of benazepril hydrochloride (2) starting from the Michael adduct (14), obtained reacting compounds of formula (11) and (13), as defined in the disclosure

This application is a 371 of PCT/EP03/04343, filed Apr. 25, 2003.

FIELD OF THE INVENTION

The present invention relates to antihypertensive agents, in particularACE-inhibitors.

PRIOR ART

Benazepril (1), namely[S—(R*,R*)]3-[[1-(ethoxycarbonyl)-3-phenylpropyl]-amino]-2,3,4,5-tetrahydro-2-oxo-1-H-1-benzazepin-1-acetic]acid,is an antihypertensive compound belonging to the class ofACE-inhibitors, which are compounds inhibiting the angiotensineconverting enzyme. Benazepril is usually employed in therapy in the formof hydrochloride (2).

The preparation of benazepril disclosed in U.S. Pat. No. 4,410,520 andJ. Med. Chem. 1985, 28, 1511–1516, reported in Scheme 1, involves thereductive amination of ethyl 2-oxo-4-phenyl butyrate (3) with(3S)-3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (4)promoted by sodium cyanoborohydride. The two resulting benazeprilisomers are obtained in a 7:3 diastereomeric ratio. Following treatmentwith hydrochloric acid gas and recrystallization, the hydrochloride isisolated in a 95:5 diastereomeric ratio and in 25% yield. The maindrawback of this method is that it requires the use of sodiumcyanoborohydride, which is a toxic reagent, and furthermore it affordsthe hydrochloride in too low a diastereomeric ratio to be marketed.

U.S. Pat. No. 4,410,520 discloses other methods for the preparation ofbenazepril, as reported in Scheme 2, which however make use ofprecursors difficult to obtain and afford diastereomeric mixturesdifficult to separate.

An alternative method to those reported above was disclosed in EP206993. It involves the nucleophilic substitution of(3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(11), using N-methylmorpholine as solvent/reagent, on the chiralsubstrate ethyl (2R)-2-(4-nitrobenzenesulfonyl)-4-phenyl butyrate (10)which is in turn prepared starting from ethyl 2-oxo-4-phenyl butyrate(3), by stereoselective hydrogenation in the presence of chiral bases(e.g. cinchonidine) (scheme 3), which step makes the whole processrather complex. The reaction between compounds (10) and (11) is carriedout at 80° C. for more than 6 hours. Treatment with hydrochloric acidgas and precipitation with ethyl acetate directly afford Benazeprilhydrochloride in a S,S:R,S=99.7:0.3 diastereomeric ratio.

DETAILED DISCLOSURE OF THE INVENTION

The present invention relates to a process for the preparation ofbenazepril hydrochloride, reported in Scheme 4, which makes use of(3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(11) as a precursor.

The process comprises the following steps:

-   a) reacting    (3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (11)    with a 3-benzoyl acrylic acid ester (13) to give the corresponding    Michael adduct (14);-   b) transforming the adduct (14) to give    3-[[1-(carboxy)-3-phenyl-propyl]-amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one    (15);-   c) crystallizing the S,S isomer of compound (15);-   d) esterifying compound (15) to give    3-[[1-(ethoxycarbonyl)-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one    (12);-   e) treating compound (12) with hydrochloric acid gas to give    benazepril hydrochloride.

In compounds of formula (13) and (14) R is a straight or branched C₁–C₆alkyl group or a benzyl group.

Step a) is carried out reacting compound (11) with compounds (13) inmolar amounts ranging from 0.5 to 2, preferably from 0.9 to 1.1, inorganic solvents selected for example from aromatic solvents, preferablytoluene, chlorinated solvents, preferably dichloromethane, esters,preferably ethyl acetate, ethers, preferably diethyl ether andtetrahydrofuran, dipolar aprotic solvent, preferably dimethylformamide,aliphatic solvents, preferably cyclohexane, alcohols, preferablymethanol, ketones, preferably acetone. According to preferredembodiments of the invention, the reaction is carried out in toluene orin ethyl acetate, most preferably in toluene. The reaction is carriedout at temperatures ranging from −10° C. to 80° C., preferably from 0°C. to 25° C. Compounds (14) are obtained in high yields and consist of amixture of two S,S and S,R diastereomers, in a ratio which mainlydepends on the solvent used, as reported in Table I for compound (14a),in which R is ethyl (obtained in a yield higher than 95%). The bestresults are obtained with a polar solvents such as toluene.

TABLE 1 Relationship between solvent - (14a) diastereomer ratio Solvent14a (R = C₂H₅) S,S/S,R isomers ratio Dichloromethane 65:35 Toluene 75:25Dimethylformamide 60:40 Methanol 58:42 Ethyl acetate 60:40 Ethyl acetateunder reflux 40:60 Cyclohexane 73:27 Water No reaction Hexane Noreaction

The Michael adduct (14) is a novel compound and is also part of thepresent invention.

The transformation of step b) can be carried out as follows:

b1) compound (14) is hydrogenated in the same solvent as used for stepa) in the presence of a catalyst selected for example from Pd, Pt, Rh,Ru, Cu, in molar amounts ranging from 0.01 to 1, preferably from 0.01 to0.1, on supports selected for example from charcoal, alumine, bariumsulfate, calcium carbonate, at temperatures ranging from −10° C. to 80°C., preferably from 0° C. to 30° C., at a hydrogen pressure ranging from1 atm to 40 atm, preferably from 2 atm to 10 atm, to give a compound offormula (16), in which R has the meanings as defined above (scheme 5).According to a preferred embodiment of the invention, the reaction iscarried out without isolating compound (14), using ethyl acetate ortoluene as solvent, preferably toluene, and Pd on charcoal as catalyst.

The resulting intermediate (16) consists of a mixture of fourdiastereomers (SSS, SRS, SSR, SRR); this compound is also novel and itforms part of the invention.

Transformation into (15) is completed preferably without isolatingcompound (16), but treating the mixture from the above reaction with amineral or organic acid and carrying out the catalytic reduction asdescribed above. The mineral acid is preferably sulfuric acid, while theorganic acid is preferably selected from acetic acid, trifluoroaceticacid, methanesulfonic acid and toluenesulfonic acid, more preferablyacetic acid.

b2) Compound (14) is hydrogenated to compound (16) as described in b1.The catalyst is filtered off, then the solution containing (16) is addedwith acetic acid in molar ratios ranging from 0.1 to 100 with respect to(16) and left to react at temperatures ranging from 0 to 120° C.,preferably from 15 to 60° C. The resulting lactone (17) is a novelcompound and is also part of the present invention.

Similarly to the parent compound (16), compound (17) consists of adiastereomeric mixture (SSS, SSR, SRR, SRS). Transformation of (17) into(15) can be carried out by catalytic hydrogenation under the sameconditions as used to transform (14) into (16) or by “hydrogen transfer”reaction. Particularly useful hydrogen donors are cyclic ethers,cyclohexene, cyclobexadiene, methylcyclohexene, limonene, dipentene,mentene, hydrazine, phosphinic acid and derivatives, indoline, ascorbicacid, formic acid and the sodium or ammonium salts thereof, secondaryalcohols such as isopropanol, in molar ratios from 1.5 to 50, preferablyfrom 1.5 to 10. The use of cyclohexene in molar ratios from 1.5 to 3 orammonium formate in molar ratios from 1 to 4 is preferred, in particularthe latter one b3) Compound (14) is treated with sodium borohydride inmolar ratios from 0.25 to 5, preferably from 0.5 to 1.5, at temperaturesfrom 0 to 80° C., preferably from 10 to 30° C. If necessary, sodiumborohydride may be dissolved by addition of methanol as cosolvent, orthe reactive can be dissolved in a 0.1 M NaOH solution, subsequentlyadding a phase transfer catalyst such as tetrabutylammonium chloride.This reaction directly affords lactone (17), which is transformed into(15) as described in b2 (scheme 7).

The resulting compound (15), consisting of a S,S and S,R diastereomericmixture, is crystallized (step c) by treatment with an organic solventselected from an aromatic solvent, preferably toluene, a chlorinatedsolvent, preferably dichloromethane, an ester, preferably ethyl acetate,an ether, preferably diethyl ether and tetrahydrofuran, a dipolaraprotic solvent, preferably dimethylformamide, an aliphatic solvent,preferably cyclohexane, an alcohol, preferably methanol or isopropanol,a ketone, preferably acetone, or a mixture thereof, either alone or withacetic acid, more preferably with dichloromethane, methanol orisopropanol or a mixture of acetone and glacial acetic acid; and thusenriched in the S,S isomer (the S,S:S,R ratio being higher than 95:5).

Step d) is carried out reacting compound (15) with carbonyldiimidazolein molar amounts ranging from 0.5 to 2, preferably from 0.9 to 1.2, inone of the same solvents as indicated for step a) except alcohols, attemperatures ranging from −10° C. to 80° C., preferably from 0° C. to25° C. According to a preferred embodiment of the invention, the solventis toluene. The reaction of compound (15) with carbonyldiimidazoleaffords two reactive species (scheme 8). A small percentage consists ofimidazolide (18), which is usually obtained by reaction ofcarbonyldiimidazole with a carboxylic acid, while the main part consistsof the activated heterocyclic compound (19), as evidenced by HPLC andNMR analysis of the mixture.

After completion of the conversion of compound (15) into the tworeactive species, ethanol is added to the reaction mixture which is leftunder stirring until complete disappearance of intermediates (18) and(19) (HPLC and NMR analysis). After evaporation of the solvents atreduced pressure, the residue is taken up with the same reactionsolvent, then washed with water and the organic phase is evaporated todryness. The resulting crude is subjected to the subsequent step.

Step e) is carried out with known methods. Preferably, the crude fromstep d) is dissolved in ethyl acetate and hydrochloric acid gas isbubbled therein at temperatures ranging from −10 to 10° C. Aftercompletion of the precipitation of benazepril hydrochloride, theresidual hydrochloric acid is removed with conventional methods, afterthat the product is crystallized from acetone. Benazepril hydrochlorideis obtained with diastereomeric purity above 99%.

The process of the present invention can also be conveniently carriedout directly reacting intermediate of formula (16) in which R is ethyl(16a), obtained as described in b1 or in b2, with carbonyldiimidazole,in one of the solvents selected from those as indicated at step d), togive ethyl3-(1-t-butoxycarbonylmethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-2-oxo-6-phenyl-[1,3]oxazinan-4-carboxylate(20), as a mixture of the four possible diastereomers (SSS, SSR, SRS,SRR). Compound (20) is a novel compound and it forms part of the presentinvention. According to this variation, illustrated in Scheme 9, step e)comprises reaction with carbonyldiimidazole, then hydrogenation ofcompound (20) under the same conditions as indicated for step b) to givecompound (12) as a S,S and S,R diastereomeric mixture. According to apreferred embodiment of the invention, step d) is carried out withoutisolating compound (16a), but filtering off the catalyst from thereaction mixture and adding carbonyldiimidazole. Analogously, compound(20) is not isolated from the mixture and, after addition of thecatalyst, is directly subjected to catalytic hydrogenation.

Afterwards, step f) is carried out as described above.

The invention is illustrated in further detail by the followingexamples.

EXAMPLES Example 1 Preparation of3-[[1-(carboxy)-3-phenyl-propyl]amino]-1-t-butoxy-carbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(15)

Ethyl 3-benzoylacrylate (13a) (55.6 g, 272 mmoles) is dropped into asolution of(3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(11) (66.2 g, 228 mmoles) in 200 ml of ethyl acetate, at roomtemperature in 1 h. The resulting mixture is left under stirring for 18h, added with 10% Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for18 h at room temperature. After completion of the reaction, 200 ml ofacetic acid are added and the mixture is hydrogenated for a further 18 hat 3 atm and at room temperature. After this time, the catalyst isfiltered off through Celite and the solvent mixture is evaporated todryness, the residue is taken up in dichloromethane (200 ml) and theresulting precipitate is filtered, washed with 20 ml of dichloromethaneand dried to give3-[[1-(carboxy)-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(15) (36 g, yield: 32%).

-   ¹H-NMR (CDCl₃, δ in ppm): 1.42 (s, 9H), 2.03 (m, 3H), 2.38 (m, 1H),    2.57 (dd, 1H), 2.75 (m, 2H), 3.07 (t, 1H), 3.23 (m, 2H), 4.32 (d,    1H), 4.57 (d, H),7.05–7.40 (aromatics, 9H).

Example 2 Preparation of3-[[1-(carboxy)-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(15)

Ethyl 3-benzoylacrylate (13a) (55.6 g, 272 mmoles) is dropped into asolution of(3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(11) (66.2 g, 228 mmoles) in 200 ml of toluene, at room temperature in 1h. The resulting mixture is left under stirring for 18 h, added with 10%Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for 18 h at roomtemperature. After completion of the reaction, 200 ml of acetic acid areadded and the mixture is hydrogenated for a further 18 h, at 3 atm atroom temperature, after that the catalyst is filtered off through Celiteand the solvent mixture is evaporated to dryness. The residue is takenup with isopropanol (500 ml) and the resulting precipitate is filtered,washed with 20 ml of dichloromethane and dried to give3-[[1-(carboxy)-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(15) (58.5 g, yield: 52%).

Example 3 Preparation of3-[[1-(carboxy)-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(15)

Ethyl 3-benzoylacrylate (13a) (55.6 g, 272 mmoles) is dropped into asolution of(3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(11) (66.2 g, 228 mmoles) in 200 ml of toluene, at room temperature in 1h. The resulting mixture is left under stirring for 18 h, then addedwith 10% Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for 18 h atroom temperature. After completion of the reaction the catalyst isfiltered off through Celite, 50 ml of acetic acid are added and thesolvent mixture is evaporated to kettle temperature of 110–120° C. Theresidue is taken up in 200 ml of toluene, 50 ml of acetic acid thencyclohexene (50 ml) and 10% Pd—C (26 g, 22 mmoles) are added. Thereaction mixture is heated to 80° C. for 18 h, after that the catalystis filtered off through Celite and solvents are evaporated off. Theresidue is taken up with isopropanol (500 ml) and the resultingprecipitate is filtered, washed with 20 ml of isopropanol and dried togive3-[[1-(carboxy)-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(15) (60.7 g, yield: 54%).

Example 4 Preparation of3-[[1-(carboxy)-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(15)

Ethyl 3-benzoylacrylate (13a) (55.6 g, 272 mmoles) is drooped into asolution of(3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(11) (66.2 g, 228 mmoles) in 200 ml of toluene, at room temperature in 1h. The resulting mixture is left under stirring for 18 h, then asolution of sodium borohydride (228 mmoles 8.6 g) and tetrabutylammoniumchloride (5.0 g) in 50 ml of 0.1 M NaOH is added and the mixture isstirred at room temperature for 18 h. The aqueous phase is separated, 50ml of acetic acid are added to the organic phase and the mixture is leftunder stirring for 30′, then added with 10% Pd—C (26 g, 22 mmoles) andammonium formate (456 mmoles, 33.3 g) and left under stirring for 4 h.Afterwards, the catalyst is filtered off through Celite and 100 ml ofwater is added. The resulting precipitate is filtered, washed with 20 mlof isopropanol and dried to give3-[[1-(carboxy)-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(15) (53.9 g, yield: 48%).

Example 5 Preparation of benazepril hydrochloride (2)

25 g (55.2 mmoles) of3-[[1-(carboxy)-3-phenyl-propyl]amino]-1-t-butoxycarbonyl-methyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(15) are suspended in 250 ml of toluene and added withcarbonyldiimidazole (10.74 g, 66.2 mols). The mixture is left understirring for 2 h, then 100 ml of ethanol are added. After reacting for 4h, solvents are evaporated off and the residue is taken up with 300 mlof toluene and 100 ml of water. The phases are separated and the organicphase is washed twice with water. Toluene is then evaporated off and themixture is taken up with 75 ml of ethyl acetate, cooled to 11° C. andHCl gas is bubbled therein. After precipitation of the product, about ⅔of the solvent are distilled off twice, adding each time fresh solventto remove the residual HCl, then the mixture is diluted with 75 ml ofacetone, cooled to 10° C. and filtered, to obtain 21.4 g of product (84%yield).

-   ¹H NMR (D₂O, 6 in ppm): 1.02 (t, 3H), 2.17 (m, 3H), 2.43 (m, 1H),    2.61 (m, 3H), 2.97 (m, 1H), 3.77 (m, 2H), 3.97 (q, 2H), 4.36 (d,    1H), 4.57 (d, 1H),7.05–7.35 (aromatics, 9H).

Example 6 Preparation of benazepril hydrochloride (2)

Ethyl 3-benzoylacrylate (13a) (55.6 g, 272 mmoles) is dropped into asolution of(3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(11) (66.2 g, 227 mmoles) in 200 ml of toluene, at room temperature in 1h. The resulting mixture is left under stirring for 18 h, then addedwith 10% Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for 18 h atroom temperature. The catalyst is filtered off and carbonyldiimidazole(272 mmoles, 44.2 g) is added. After reacting for 4 h the mixture iswashed 3 times with 100 ml of water, added again with 10% Pd—C (26 g, 22mmoles) and hydrogenated at 1 atm for 18 h at room temperature. Afterthat the catalyst is filtered off, the solvent is evaporated off and theresidue is taken up with 240 ml of ethyl acetate, cooled to 10° C. andHCl gas is bubbled therein to complete precipitation of the product.About ⅔ of the solvent is distilled off twice, adding each time freshsolvent to remove the residual HCl. The mixture is then diluted with 75ml of acetone, cooled to 10° C. and filtered, to obtain 32 g of product(31% yield).

-   ¹H NMR (D₂O, δ in ppm): 1.02 (t, 3H), 2.17 (m, 3H), 2.43 (m, 1H),    2.61 (m, 3H), 2.97 (m, 1H), 3.77 (m, 2H), 3.97 (q, 2H), 4.36 (d,    1H), 4.57 (d, 1H),7.05–7.35 (aromatics, 9H).

Example 7 Preparation of3-[[1-(ethoxycarbonyl)-3-oxo-3-phenyl-propyl]-amino]-1-t-butyl-oxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(14)

Ethyl 3-benzoylacrylate (13a) (55.6 g, 272 mmoles) is dropped into asolution of(3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(11) (66.2 g, 227 mmoles) in 200 ml of toluene, at room temperature in 1h. The resulting mixture is left under stirring for 18 h, then solventis evaporated off and the residue is purified by chromatography (eluenthexane-ethyl acetate 7:3). Two isomeric products are isolated.

Isomer 1 (first eluted)—minor product (SR):

-   ¹H-NMR (CDCl₃, 6 in ppm): 1.17 (t, 3H), 1.40 (s, 9H), 1.92 (m, 1H),    2.30 (m, 1H), 2.55 (dd, 1H), 3.32 (m,4H), 3.72 (t, 1H), 4.08 (q,    2H), 4.23 (d, 1H), 4.66 (d, 1H),7.05–8.00 (aromatics, 9H).

Isomer 2 (second eluted)—main product (SS):

-   ¹H-NMR (CDCl₃, δ in ppm): 1.05 (t, 3H), 1.40 (s, 9H), 1.98 (m, 1H),    2.38 (m, 1H), 2.57 (dd, 1H), 3.35 (m, 4H), 3.64 (t, 1H), 4.02 (q,    2H), 4.24 (d, 1H), 4.53 (d, 1H),7.05–8.00 (aromatics, 9H).

Example 8 Preparation of3-[[1-(ethoxycarbonyl)-3-hydroxy-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(16)

Ethyl 3-benzoylacrylate (13a) (55.6 g, 250 mmoles) is dropped into asolution of(3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(11) (66.2 g, 227 mmoles) in 200 ml of toluene, at room temperature in 1h. The resulting mixture is left under stirring for 18 h, then addedwith 10% Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for 18 h atroom temperature. The solvent is evaporated off and the residue ispurified by chromatography (eluent: hexane-ethyl acetate 7:3). A mixtureof isomeric products is isolated.

-   ¹H-NMR (CDCl₃, 8 in ppm): 1.03–1.32 (m, 3H), 1.40 (m, 9H), 1.73–1.93    (m, 1H), 1.95–2.15 (m, 1H), 2.38–2.63 (m, 2H), 3.18–3.43 (m,4H),    3.98–4.12 (m, 2H), 4.25–4.60 (m, 2H), 4.68–5.20 (m, 1H), 7.05–7.40    (aromatics, 9H).

Example 9 Preparation of ethyl3-(1-t-butoxycarbonylmethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)2-oxo-6-phenyl-[1,3]oxazinan-4-carboxylate(20)

Ethyl 3-benzoylacrylate (13a) (55.6 g, 250 mmoles) is dropped into asolution of(3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(11) (66.2 g, 227 mmoles) in 200 ml of toluene, at room temperature in 1h. The resulting mixture is left under stirring for 18 h, then addedwith 10% Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for 18 h atroom temperature. The catalyst is filtered off and carbonyldiimidazole(272.4 mmoles, 44.16 g) is added. After reacting for 4 h the mixture iswashed 3 times with 100 ml of water. After completion of the reactionthe solvent is evaporated off and the residue is purified bychromatography (eluent: hexane-ethyl acetate 7:3). A mixture of isomericproducts is isolated.

-   ¹H-NMR (CDCl₃, 8 in ppm): 1.03–1.32 (m, 3H), 1.40 (m, 9H), 1.83–2.40    (m, 5H), 3.05–3.37 (m, 3H), 3.95–4.08 (m, 2H), 4.17–4.62 (m, 2H),    5.90–6.20 (m, 1H), 7.05–7.40 (aromatics, 9H).

Example 10 Preparation of[2-oxo-3-(2-oxo-5-phenyl-tetrahydro-furan-3-ylamino)-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl]-aceticacid tert-butyl ester (17)

Ethyl 3-benzoylacrylate (13a) (55.6 g, 250 mmoles) is dropped into asolution of(3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(11) (66.2 g, 227 mmoles) in 200 ml of toluene, at room temperature in 1h. The resulting mixture is left under stirring for 18 h, then addedwith 10% Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for 18 h atroom temperature. After completion of the reaction, the catalyst isfiltered off, 50 ml of acetic acid are added and volatiles are distilledoff at 110–120° C. inner temperature.

The residue is purified by chromatography (eluent: hexane-ethyl acetate7:3) to obtain a mixture of isomeric products.

-   ¹H-NMR (CDCl₃, 6 in ppm): 1.45 (m, 9H), 1.82–2.15 (m, 2H), 2.41–2.63    (m, 3H), 3.18–3.43 (m, 1H), 3.18–3.95 (m, 2H), 4.25–4.60 (m, 2H),    5.15–5.70 (m, 1H),7.05–7.40 (aromatics, 9H).

Example 11 Preparation of3-[[1-(carboxy)-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(15)

Ethyl 3-benzoylacrylate (13a) (55.6 g, 272 mmoles) is dropped into asolution of(3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(11) (66.2 g, 228 mmoles) in 200 ml of toluene, at room temperature in 1h. The resulting mixture is left under stirring for 18 h, then addedwith 10% Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for 18 h atroom temperature. After completion of the reaction the catalyst isfiltered off through Celite, 100 ml of acetic acid are added and thesolvent mixture is reacted at 20–30° C. for 18 h. After lactonization tocompound (17), ammonium formate (51.4 g, 816 mmoles) and 10% Pd—C (26 g,22 mmoles) are added. The reaction mixture is heated to 40° C. for 3 h,after that the catalyst is filtered off through Celite and solvents areevaporated off. The residue is taken up with acetone (600 ml) and aceticacid (200 ml), heated to dissolution and cooled. The resultingprecipitate is filtered, washed with 80 ml of acetone1 and dried to give3-[[1-(carboxy)-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(15) (60.7 g, yield: 54%).

1. A process for the preparation of benazepril hydrochloride (2),

comprising the following steps: a) reacting(3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(11)

with a 3-benzoyl acrylic acid ester (13)

in which R is a straight or branched C₁–C₆ alkyl group or a benzylgroup, to give a Michael adduct of formula (14)

in which R has the meanings as defined above; b) transforming compound(14) into3-[[1-(ethoxycarbonyl)-3-hydroxy-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(15)

c) crystallizing the S,S isomer of compound (15); d) esterifyingcompound (15) to give3-[[1-(ethoxycarbonyl)-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one(12); and

e) treating compound (12) with hydrochloric acid gas to give benazeprilhydrochloride (2).
 2. A process as claimed in claim 1 wherein R isethyl.
 3. A process as claimed in claim 1 wherein step b) is carried outwithout isolating compound (14).
 4. A process according to claim 1wherein step b) comprises: catalytic hydrogenation of compound (14) togive an intermediate of formula (16)

in which R has the meanings as defined above; and catalytichydrogenation of compound (16) in the presence of a mineral or organicacid to give compound (15).
 5. A process as claimed in claim 4 whereinthe mineral acid is sulfuric acid and the organic acid is acetic acid.6. A process as claimed in claim 1 wherein step b) comprises: catalytichydrogenation of compound (14) to give compound (16); conversion ofcompound (16) to lactone (17); and

conversion of compound (17) to compound (15) by catalytic hydrogenationor by hydrogen transfer reaction.
 7. A process as claimed in claim 6wherein compound (16) is converted to lactone (17) by addition of aceticacid and heating to a temperature ranging from 0° C. to 120° C.
 8. Aprocess as claimed in claim 6 wherein compound (14) is directlyconverted to lactone (17) by reduction with sodium borohydride.
 9. Aprocess as claimed in claim 4 wherein the catalyst is Pd supported oncharcoal.
 10. A process as claimed in claim 6 wherein the hydrogentransfer reaction comprises the use of a hydrogen donor selected fromcyclic ethers, cyclohexene, cyclohexadiene, methylcyclohexene, limonene,dipentene, mentene, hydrazine, phosphinic acid and derivatives,indoline, ascorbic acid, formic acid and the sodium or ammonium saltsthereof, secondary alcohols.
 11. A process as claimed in claim 10wherein the hydrogen donor is ammonium formate.
 12. A process as claimedin claim 1, wherein step c) crystallization is carried out in a mixtureof acetone and acetic acid, as solvent.
 13. A process as claimed inclaim 1 wherein steps a) and b) are carried out in a solvent selectedfrom toluene, dichloromethane, ethyl acetate, diethyl ether,tetrahydrofuran, dimethylformamide, cyclohexane, methanol and acetone,and step d) is carried out in a solvent selected from toluene,dichloromethane, ethyl acetate, diethyl ether, tetrahydrofuran,dimethylformamide, cyclohexane and acetone.
 14. A process as claimed inclaim 13, wherein the solvent is toluene.
 15. A process as claimed inclaim 1 wherein step d) is carried out reacting compound (15) withcarbonyldiimidazole and ethanol.
 16. A process as claimed in claim 4wherein compound (16) in which R is ethyl is treated withcarbonyldiimidazole to give ethyl3-(1-t-butoxycarbonylmethyl-2-oxo-2,3,4,5-tetrahydro-1Hbenzo[b]azepin-3-yl)-2-oxo-6-phenyl-[1,3]oxazinan-4-carboxylate (20)

which is subjected to catalytic reduction to give compound (12).
 17. Aprocess according to any one of claim 1 wherein the catalytic reductionsor hydrogen transfer reactions are carried out in the presence of acatalyst selected from Pd, Pt, Rh, Ru, Cu on a support selected fromcharcoal, alumine, barium sulfate, calcium carbonate.
 18. A process asclaimed in claim 16 wherein the catalytic reduction is carried outwithout isolating compound (20).
 19. A compound selected from the groupconsisting of:

in which R is a straight or branched C₁–C₆ alkyl group or a benzylgroup.